This application is a 371 of PCT/EP98/07532 filed Nov. 23, 1998.
The present invention relates to novel aminobenzothiazole derivatives, to a process for their preparation, to pharmaceutically acceptable compositions comprising them and to the use of said compounds in the prevention and/or treatment of acute or chronic neurodegenerative disorders.
According to W. Danysz et al., DNandP 8(5), June 1995, excitatory amino acid (EAA) glutamate is a broad spectrum agonist at the major neuronal EAA receptor sites. Although glutamate is a very important element in governing physiological balance within the central nervous system (CNS), under certain conditions excessive activation of glutamate receptors is neurotoxic. It is now clear that not only exogenously given excitotoxins but also endogenous glutamate or other similar agonists can kill neurons under certain pathological conditions called xe2x80x9cexcitotoxicityxe2x80x9d. It has been implied that excitotoxicity is involved in many types of acute neurodegenerative disorders such as, for example, ischemia, hypoglycemia or hypoxia and chronic neurodegenerative disorders such, for example, Huntington""s, Parkinson""s and Alzheimer""s diseases, AIDS-dementia, hepatic encephalopaty, amyotrophic lateral sclerosis, epilepsy-related damage, olivopontocerebellar atrophy, Tourette""s syndrome, CNS pathology related to measles virus, infection and motor neuron disease.
Agents able to modulate or antagonize the neurotoxic effect of an endogenous excitatory amino acid (EAA) or a similar compound at the CNS level can therefore be useful as neuroprotective agents for the prevention and/or treatment of an acute or a chronic neurodegenerative disease.
There is therefore a need to find pharmacological substances which exert a control of the above mentioned neuropathological processes by means of their activity as mediators or inhibitors of the effects of said neurotoxic agents.
The present invention fulfill such a need.
Accordingly, the present invention provides a 2-aminobenzothiazole derivative of formula (I) 
if the case either as single isomer or as mixture of isomers,
wherein
X is CO, Cxe2x95x90NOH, CHOH or CH2;
Y is CH2 or
CHCH2R2 in which
R2 is hydrogen, hydroxy, phenoxy, amino, N(CH3)2, OCOR4 in which R4 is C1-C6 alkyl or a group of formula (i) 
wherein R1 is hydrogen, halogen, cyano, a linear or branched C1-C5 alkyl group, a linear or branched C1-C5 alkoxy group or trifluoromethyl; or
R2 is NHR3 in which R3 is a linear or branched C2-C6 alkanoyl group, a linear or branched C1-C6 alkylsulfonyl group, trifluoromethanesulfonyloxy, or a group of formula (i) or (ii) 
wherein R1 is as defined above;
Z is a (CH2)n group wherein n is zero or an integer from 1 to 4; CHOH; CO; O; S; SO2 or a group of formula (iv) 
wherein R1 is as defined above;
provided that :
when X is CO, R2 is not hydroxy;
or a pharmaceutically acceptable salt thereof.
Depending on the precise meaning of the substituent(s) X and/or Y, the compounds of formula(I) can have one or more asymmetric centers and therefore can exist in different stereoisomers. For example, a compound of formula (I) which possesses one asymmetric center can exist either as a pure optical isomer or as racemic mixture; and a compound of formula (I) which possesses two, not equivalent, asymmetric centers wherein one of the substituents is the same, can exist as a threo or an erithro pure optical isomer or as threo or erithro racemic mixture.
Both the racemic mixture and the pure optical isomers of a compound of formula (I) are within the scope of the invention.
The present invention further comprises pharmaceutically acceptable salts of the compounds of formula (I) with pharmaceutically acceptable inorganic acids such as, e.g., hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid and organic acids such as, e.g., malic, maleic, pamoic, succinic, gluconic, citric, tartaric, ascorbic, acetic, methanesulphonic or benzensulphonic acid.
A linear or branched C2-C6 alkyl group may be, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl sec-butyl, tert-butyl or n-pentyl; preferably it is methyl, ethyl or n-propyl.
A linear or branched C1-C5 alkoxy group may be, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy or sec-butoxy; preferably, it is methoxy or ethoxy.
A linear or branched C2-C4 alkanoyl group may be, for example, acetyl, propanoyl, isobutirroyl, valeroyl; preferably, it is acetyl or propanonyl.
A linear or branched C1-C6 alkylsulfonyl group may be, for example, methanesulphonyl, ethanesulphonyl or propanesulphonyl; preferably, it is a linear C1-C3 alkylsulfonyl group, in particular methanesulphonyl ot ethanesulphonyl.
In a group of formula (i), (ii), (iii) or (iv), the substituent R1, which may be in position orto, meta, or para of the phenyl ring is, preferably, in position para.
Preferably, R1 is hydrogen or halogen, in particular fluorine.
A preferred class of compounds of the invention are compounds of formula (I), if the case either as singie isomers or as mixture of isomers, wherein
X is CO, CHOH or CH2;
Y is CH2 or CHCH2R2 wherein R2 is hydrogen, hydroxy, phenoxy, N(CH3)2 or wherein R2 is NHR3 in which R3 is a linear C1-C3 alkylsulfonyl group, a group of formula (ii) or (iii) as defined above in which R1 is hydrogen;
Z is a (CH2)n group wherein n is 1, CO, O, S or a group of formula (iv) as defined above in which R1 is hydrogen or halogen;
R1 is as defined above;
provided that:
when X is CO, Y is not hydroxy; and the pharmaceutically acceptable salts thereof.
Examples of specific compounds of the invention are:
1)1-Hydroxymethyl-1-(4-benzylpiperidin-1-yl)-2-hydroxy-2-(2-aminobenzothiazol-6-yl)-ethane;
2)1-Phenoxymethyl-1-(4-benzylpiperidin-1-yl)-2-hydroxy-2-(2-aminobenzothiazol-6-yl)-ethane;
3)1-Dimethylaminomethyl-1-(4-benzylpiperidin-1-yl)-2-hydroxy-2-(2-aminobenzothiazol-6-yl)-ethane;
4)1-Benzoylaminomethyl-1-(4-benzylpiperidin-1-yl)-2-hydroxy-2-(2-aminobenzothiazol-6-yl)-ethane;
5)1-Methanesulphonylaminomethyl-1-(4-benzylpiperidin-1-yl)-2-hydroxy-2-(2-aminobenzothiazol-6-yl)-ethane;
6)1-Phenylsulphonylaminomethyl-1-(4-benzylpiperidin-1-yl)-2-hydroxy-2-(2-aminobenzothiazol-6-yl)-ethane;
7)1-(2-Amino-benzothiazol-6-yl)-2-(4-benzyl-piperidin-1-yl)-propan-1-ol;
8)1-(2-Amino-benzothiazol-6-yl)-2-(4-benzyl-piperidin-1-yl)-propane;
9)1-(2-Amino-benzothiazol-6-yl)-2-(4-benzyl-piperidin-1-yl)-ethane;
10)1-(2-Amino-benzothiazol-6-yl)-2-(4-phenoxy-piperidin-1-yl)-ethane;
11)1-(2-Amino-benzothiazol-6-yl)-2-(4-phenylthio-piperidin-1-yl)-ethane;
12)1-(2-Amino-benzothiazol-6-yl)-2-(4-benzoyl-piperidin-1-yl)-ethane;
13)1-(2-Amino-benzothiazol-6-yl)-2-(4-(4,4xe2x80x2-difluorodiphenylmethyl-piperidin-1-yl)-ethane;
14)1-(2-Amino-benzothiazol-6-yl)-3-phenoxy-2-(4-benzyl-piperidin-1-yl)-propan-1-one;
15)1-(2-Amino-benzothiazol-6-yl)-3-dimethylamino-2-(4-benzyl-piperidin-1-yl)-propan-1-one;
16)1-(2-Amino-benzothiazol-6-yl)-3-benzoylamino-2-(4-benzyl-piperidin-1-yl)-propan-1-one;
17)1-(2-Amino-benzothiazol-6-yl)-3-methanesulphonylamino-2-(4-benzyl-piperidin-1-yl)-propan-1-one;
18)1-(2-Amino-benzothiazol-6-yl)-3-phenylsulphonylamino-2-(4-benzyl-piperidin-1-yl)-propan-1-one;
19)2-(4-Benzylpiperidin-1-yl)-1-(2-amino-benzothiazol-6-yl)-propan-1-one;
20)2-(2-Benzoylpiperidin-1-yl)-1-(2-aminobenzothiazol-6-yl)-propan-1-one;
21)1-(2-Aminobenzothiazol-6-yl)-2-(4-benzyl-piperidin-1-yl)-ethanone;
22)1-(4-Benzoylpiperidin-1-yl)-2-(2-amino-benzothiazol-6-yl)-ethanone;
23)1-(4-Phenoxypiperidin-1-yl)-2-(2-amino-benzothiazol-6-yl)-ethanone;
and their pharmaceutically acceptable salts;
if the case,when one asymmetric center is present on the molecule, either as a pure optical isomer or as racemic mixture; or when two, not equivalent, asymmetric centers wherein a substituent is the same, are present on the molecule, either as a threo or an erithro pure optical isomer or as threo or erithro racemic mixture.
A compound of formula (I), if the case, either as pure optical isomer or as racemic mixture, can be prepared by a process which comprises:
a) reacting a compound of formula (II) 
if the case, either as pure optical isomer or as racemic mixture, wherein W is hydrogen or methyl and Hal is a halogen atom;
with a compound of formula (III) 
wherein
Z is a (CH2)n group wherein n is zero or an integer from 1 to 4, CHOH, CO, O, S, SO2 or a group of formula (iv) 
wherein R1 is hydrogen, halogen, cyano, a linear or branched C1-C5 alkyl group, a linear or branched C1-C5 alkoxy group or trifluoromethoxy;
to obtain a compound of formula (I), if the case, either as a pure optical isomer or as racemic mixture, wherein Z and R1 are as defined above, X is CO and Y is CH2 or CHCH2R2 in which R2 is hydrogen; and, if desired,
b) converting a compound of formula (I) as obtained under step a), into another compound of formula (I) wherein Y, Z and R1 are as defined above and X is CHOH; or
c) converting a compound of formula (I) as obtained under step a), into another compound of formula (I) wherein Y, Z and R1 are as defined above and X is CH2; or
d) converting a compound of formula (I) as obtained under step a), into another compound of formula (I) wherein Y, Z and R1 are as defined above and X is Cxe2x95x90NOH; or
e) condensing a compound of formula (IV) 
if the case, either as pure optical isomer or as racemic mixture, with a compound of formula (V) 
wherein Hal, Z and R1 are as defined above, to obtain a compound of formula (VT) 
if the case either as a pure optical isomer or as racemic mixture, wherein Z and R1 are as defined above;
f) converting a compound of formula (VI) as obtained under step e), to obtain a compound of formula (VII) 
if the case either as a pure optical isomer or as racemic mixture, wherein Z and R1 are as defined above, J is hydroxy or phenylthio and Jxe2x80x2 is amino, N(CH3)2 phenoxy, phenylthio, OCOR4 in which R4 is C1-C6 alkyl or a group of formula (i) 
wherein R1 is as defined above, or Jxe2x80x2 in NHR3 in which R3 is is a linear or branched C2-C6alkanoyl group, a linear or branched C1-C6 alkylsulfonyl group, trifluoromethanesulphonyloxy or a group of formula (ii) or (iii) 
wherein R1 is as defined above;
g) reducing a compound of formula (VII) to obtain a compound of formula (VIII) 
if the case, either as a pure optical isomer or as racemic mixture, wherein J is hydroxy or hydrogen, Z and R1 are as defined above and Jxe2x80x2 is hydrogen, phenoxy, N(CH3)2, OCOR4 in which R4 is as defined above, or Jxe2x80x2 is NHR3 in which R3 is as defined above;
h) converting a compound of formula (VIII) into a compound of formula (I), if the case, either as a pure optical isomer or as racemic mixture, wherein Z and R1 are as defined above, X is CHOH or CH2 and Y is CHCH2R2 in which R2 is hydrogen, phenoxy, N(CH3) 2, OCOR4 in which R4 is as defined above, or Jxe2x80x2 is NHP3 in which R3 is as defined above; and, if desired,
i) converting a compound of formula (I) if the case, either as a pure optical isomer or as racemic mixture, wherein Z, R1 and X are as defined above and Y is CHCH2R2 wherein R2 is NHR3 in which R3 is a linear or branched C2-C6 alkanoyl group or a group of formula (ii) as defined above, into another compound of formula (I) wherein Z, R1 and X are as defined above and Y is CHCH2R2 wherein R2 is amino, and, if desired,
j) converting a compound of formula (I) as obtained under step h) or i) into another compound of formula (I) wherein Y, Z and R1 are as defined above and X is Cxe2x95x90Oxe2x80x94;
and, if desired, converting a compound ot formula (I) into a pharmaceutically acceptable salt thereof.
In a compound of formula (II) or (V) a halogen atom is bromine, chlorine or iodine; preferably it is bromine.
When a compound of formula (IV) is an optically pure threo or erithro isomer, the whole synthetic procedure do not affect the chirality of the stereo center/s which is/are mantained on the end product.
The reaction described as step al comprises a nucleophilic displacement of a suitable xcex1-halogen ketone of formula (II) with a piperidine derivative of formula (III), followed by the amide hydrolysis.
The nucleophilic displacement can be carried out, for example, in presence of a proton scavenger such as, e.g., triethylamine (TEA), K2CO3 or ethyldiisopropylamine (Hxc3xcnig""s base), in a solvent such as, e.g., dimethylformamide (DMF), dimethylsolfoxide (DMSO), EtOH or tetrahydrofuran (THF), at a temperature ranging from about 40xc2x0 C. to about 100xc2x0 C.
The amide hydrolysis is generally carried out with a base such as, e.g., 1 M NaOH solution or K2CO3, in a solvent such as, e.g. EtOH or dioxane, at a temperature ranging from about 50xc2x0 C. to about 110xc2x0 C.
The conversion of a compound of formula (I) as obtained in step a), into another compound of formula (I) wherein X is CHOH, described as step b), may be carried out, for example, by employing a reducing agent such as, e.g. LiAlH4, in a solvent such as, e.g., THF, diethyl ether or dioxane, or employing a reducing agent such as, e.g. NaBH4, in a solvent such as, e.g., THF, dioxane, ethanol or isopropanol, at a temperature ranging from about xe2x88x925xc2x0 C. to about 35xc2x0 C.; preferably, the reaction described as step b) may be performed by using NaBH4 in ethanol, at a temperature ranging from about xe2x88x925xc2x0 C. to about 35xc2x0 C.
The conversion of a compound of formula (I) as obtained in step a), into another compound of formula (I) wherein X is CH2, described as step c), may be carried out, for example, by employing as reducing agent, e.g. triethylsilane in trifluoroacetic acid, at a temperature ranging from about xe2x88x9215xc2x0 C. to about 25xc2x0 C.
The conversion of a compound of formula (I) as obtained in step a), into another compound of formula (I) wherein X is Cxe2x95x90NOH, described as step o) may be carried out, for example, by reaction with hydroxylamine hydrochloride in pyridine or in presence of a proton scavenger such as, e.g. sodium acetate in ethanol/water, at a temperature ranging from about 25xc2x0 C. to about 80xc2x0 C.
Alternatively, a compound of formula (I) wherein X is CH2; Y is CH2 or CHCH2R2 in which R2 is hydrogen; R1 is hydrogen, halogen, cyano, a linear or branched C1-C5 alkyl group, a linear or branched C1-5 alkoxy group or trifluoromethyl and Z is a (CH2)n group wherein n is zero or an integer from 1 to 4, CHOH, CO, O, S, SO2 or a group of formula (iv) 
wherein R1 is as defined hereabove, may be obtained reacting a compound of formula (IX) 
wherein W is hydrogen or methyl and Hal is a halogen atom, preferably a bromine atom, with a compound of formula (III) as defined above, in the presence of a base such as, e.g., TEA, K2CO3 or ethyldiisopropylamine, in a solvent such as, e.g. ethanol or DMF, at a temperature ranging from about 25xc2x0 C. to about 75xc2x0 C., further hydrolysing the amide group by saponification, for example, by means of a base such as, e.g. KOH or K2CO3, in a solvent such as, e.g. ethanol or THF, at a temperature ranging from about 35Cxc2x0 C. to about 75xc2x0 C.
The condensation of a compound of formula (IV) with a compound of formula (V) described as step e) may be carried out, for example, in presence of a base such as, e.g., TEA, Hxc3xcnig""s base or K2CO3, in a solvent such as, e.g. DMF or dioxane, at a temperature ranging from about 50xc2x0 C. to about 100xc2x0 C.
The conversion described as step f) may be carried out, for example, by reacting a compound of formula (VI) with triphenylphosphine/diethylazodicarboxilate/phenol, triphenylphosphine/diethylazodicarboxilate/phtalimide, diphenyldisulfide/tributylphosphine or triphenylphosphine/diethylazodicarboxylate/R4xc2x0 COOH wherein R4 is as defined above, in a solvent such as, e. g. THF or dioxane, at a temperature ranging from about 20xc2x0 C. to about 100xc2x0 C.
In particular, a compound of formula (VII) wherein Jxe2x80x2 is an amino group may be obtained by reaction of a compound of formula (VI) with triphenylphosphine/diethylazodicarboxilate/phalimide, further adding to the reaction mixture hydrazine hydrate in ethanol at 50xc2x0 C.
When in a compound of formula (VII) Jxe2x80x2 is amino, it can be further transformed into a group of formula NHR3, wherein R3 has the meanings before mentioned,for example, by reaction with an appropiate C2-C6 alkanoyl, C1-C6 alkylsulfonyl or trifluoromethanesulphonyl halide or a suitable campound of formula (X) or (XI) 
wherein Hal is a halogen atom, preferably chlorine and R1 is as defined above, in a solvent such as, e.g. pyridine or dichloromethane in presence of TEA, at a temperature ranging from about 0xc2x0 C. to about 35xc2x0 C.
The reduction described as step g) may be carried out, for example, by means of a reducing agent such as, e.g. Fe or Zn in hydrochloric acid; SnCl2 in a hydrochloric acid solution; or by a catalitic hydrogenation, for example with hydrogen, in presence of a catalyst such as, e.g. Pd/C, in a solvent such as e.g. ethanol, at a pressure which may vary from about 1 atm to about 5 atm, at a temperature ranging from 25xc2x0 C. to 50xc2x0 C.
In particular, when reducing a compound of formula (VII) wherein J and Jxe2x80x2 are both phenylthio, a compound of formula (VIII) wherein J is hydrogen and Jxe2x80x2 is hydrogen can be obtained. Preferably, this reduction is accomplished by catalytic hydrogenation at about 2 atm employing Nickel Raney as a catalyst, in a solvent such as, e.g. ethanol.
The conversion described as step h) may be carried out, for example, by reaction with (SCN)2, generated by action of, e.g. Br2 or CuSO4 on KSCN in glacial acetic acid, at a temperature of about 25xc2x0 C.
The conversion described as step i) may be carried out, for example with a base, for example an inorganic base such as, e.g., NaOH or K2CO3 in a solvent such as, e.g. EtOH or dioxane, at a temperature ranging from about 50xc2x0 C. to about 110xc2x0 C.
The conversion of a compound of formula (I) wherein X is CHOH into another compound of formula (I) wherein X is Cxe2x95x90O described under step j) may be carried out, for example, by reaction with DMSO/ trifluoroacetamide (TFAA)/TEA at c temperature ranging from about xe2x88x9278xc2x0 C. to about 0xc2x0 C.
The conversion of a compound of formula (I) into a pharmaceutically acceptable salt thereof may be carried out following procedures well known in the art. For example, a pharmaceutically acceptable salt of a compound of formula (I) may be obtained combining a compound of formula (I) with at least one molar equivalent of a suitable pharmaceutically acceptable acid as defined above, in a solvent such as, e.g, ethanol or chloroform.
As stated above, the compounds of formula (I) can exist in different stereoisomers.
The stereoisomers can be separated from he corresponding mixture of stereoisomers, following methods well known in the art. For example, the racemate can be resolved into the two enantiomers by crystallization of the diastereomeric acid addition salts obtained via an optically active acid such as, e.g., tartaric, dibenzoyltartaric, camphoric or camphorsulphonic acid. In particular, when in a compound of formula (I) the substituent X is CHOH, the racemic mixture can be resolved by conversion into the diastereomeric ester or carbamate using an appropriate optically active activated acid derivative or isocyanate. After separation of the diastereoisomers by crystallization or chromatography, the pure enantiomers are recovered by saponification or by alcoholysis.
In alternative, the optically active compounds of formula (I) can be prepared in a stereoselective manner either starting from optically pure material or using optically active reagents, following methods widely reported in literature.
Both the racemic mixtures and the pure optical isomers of the compounds of formula (I) are within the scope of the invention.
The compounds of formula (II) can be prepared following procedures well known in the art starting from commercially available compounds.
The compounds of formula (III) are commercially available compounds or can be prepared following procedures well known in the art starting from commercially available compounds.
The compounds of formula (IV) are commercially available compounds.
The compounds of formula (IX) (X) and (XI) can be prepared following procedures well known in the art starting from commercially available compounds.
The compounds of formula (I) and their pharmaceutically acceptable salts possess selective neuroprotective activity.
The efficacy of the compounds of the invention as neuroprotective agents was evaluated in mixed cortical neuronal cultures, following the method reported below.
Mixed cortical neuronal cultures from foetal rats at 16 days of gestation were prepared as described by Choi (j. Neur. Sci. 7: 357-368, 1987). Briefly dissociated cells were plated on poly-L-lysine coated multiwell plates at density of 1*105 cells/cm2 in MEM with Earle""s salts supplemented with 21 mM D-glucose, 2 mM L-glutamine, 50 xcexcg/ml Streptomicin, 50 IU Penicillin, 10% Foetal Calf Serum and 10% Horse Serum. Cultures were kept at 37xc2x0 C., 5% CO2 and survived about 5 weeks. After 7 days in vitro, astrocites proliferation was inhibited by adding 10 xcexcM Cytosine Arabinoside for 48 hours; the medium was subsequently substituted twice a week with a fresh medium without foetal call serum (Hatley, J. Pharm. and Exp. Ther. 250 (II);752-758, 1989).
Only nature cortical cultures, from 14 DIV on, were used for the study. Experiments were performed at 25xc2x0 C. as follows: cells were washed once with a Locke""s buffer, (128 mM NaCl, 25 nM KCl, 1.2 mM Na2HPO4, 2.7 mM CaCl2, 20 mM Hepes and 10 mM D-glucose) pH=7.4, then preincubated with the test compounds for 3 min. followed by a 20 min. exposure to N-methyl-D-aspartate (NMDA) (500 xcexcM).
The incubation was stopped by removing Locke""s buffer and substituting the conditioned medium. After 24 hours at 37xc2x0 C., 5% CO2, Trypan Blue Dye Exclusion Test (0.04%) was used for evaluating the cells viability.
As an example, the neuroprotective effects in the above cultured cortical neurons of 1-(2-Amino-benzothiazol-6-yl)-2-(4-benzyl-piperidin-1-yl)-ethane (compound of Example 15), were tested in comparision with the neuroprotective effects of Eliprodil, a known neuroprotective agent.
The obtained results are reported in the following Table 1.
The above tabulated data clearly demonstrate, not only that the representative compound of the present invention is particularly effective as neuroprotective agent by virtue of its ability to prevent the neurotoxic action of the EAA glutamic acid, but also that its neuroprotective activity is superior (more than three times) than that one exibited by the reference compound Eliprodil.
For the above reasons, the compounds of the present invention can be useful as neuroprotective agents in the prevention and/or treatment of an acute or a chronic neurodegenerative disease, associated with the neurotoxic effect of an EAA or a similar compound. For example, the compounds of the present invention can be useful in the prevention and/or treatment of an acute neurodegenerative disorder such as, for example, ischemia, hypoglycemia or hypoxia and chronic neurodegenerative disorder such, for example, Huntington""s, Parkinson""s and Alzheimer""s diseases, AIDS-dementia, hepatic encephalopaty, amyotrophic lateral sclerosis, epilepsy, olivopontocerebellar atrophy, Tourette""s syndrome, CNS pathology related to measles virus, infection or motor neuron disease.
The compounds of this invention can be administered to a mammalian such as a human, in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film-coated tablets, liquid solutions or suspension; rectally, in the form of suppositories; parenterally, e.g. intramuscularly, by intravenous injection or infusion.
These compounds will be preferably administered in a daily dose generally in a range from about 0.1 mg to about 25 mg per kilogram of body weight per day. A suitable dose can be administered, in sub-doses per day.
The active compound is usually administered in a pharmaceutically acceptable composition.
A pharmaceutical composition according to the invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, in association with a pharmaceutically acceptable excipient (which can be a carrier or adiluent). The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form. For example, the solid oral form may contain, together with the active compound, diluents, e.g. lactose, dextrose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatins, methylcellulose or polyvinyl pirrolidone; and, in general, non toxic and inactive substances used in pharmaceutical formulations.
These pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coated, or film-coating processes. The liquid dispersion for oral administration, may be e.g. syrups, emulsions or suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol. The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectine or polyvinyl alcohol. The suppositories may contain together with the active compound a pharmaceutically acceptable carrier, e.g. cocoa-butter,or polyethylen glycol.